Autoimmune diseases are devastating and crippling diseases, and occur when a patient's own immune system turns against itself by attacking the patient's own body or tissues. One example of an autoimmune disease is systemic lupus erythematosus (SLE), which is characterized by multi-organ involvement and immunological abnormalities that include the presence of autoreactive T cells and B cells. Autoantibodies against the nucleosome appear to be a hallmark characteristic of SLE and suggest that inappropriate handling of dying (apoptotic) cells may represent a key pathogenic event in the development of SLE. SLE results from the dysregulation of both the humoral and the cellular limbs of the immune system indicating that the initial alteration may be at the level of cells that enroll and control the immune effectors, namely the dendritic cells (DCs).
Dendritic cells (DCs) are specialzed antigen presenting cells which elicit T cell mediated immune responses (Steinman, R. M. (1991) Ann. Rev. Immunology, Vol. 9, pp. 271-296 and Banchereau et al. (2000) Ann. Rev. Immunol. 18:767). DCs induce and sustain immune responses and have been shown to capture dying cells and present their antigens to CD4+ T cells, which then activate other immune effectors including B cells. DC progenitors in the bone marrow give rise to circulating precursors that home to the tissue where they reside as immature cells with high phagocytic capacity. Upon tissue damage, DCs capture antigen (Ag) and subsequently migrate to the lymphoid organs where they select rare Ag-specific T cells, thereby initiating immune responses. DCs present antigen to CD4+ T cells which in turn regulate the immune effectors including antigen-specific ones such as CD8+ T cells and B cells as well as nonspecific ones such as macrophages, eosinophils and NK cells. DCs can also directly activate B cells and induce their differentiation into plasma cells in vitro.
Three subsets of DC precursors (“DCpre”) circulate in the blood: (1) CD14+ monocytes, (2) CD11c+ myeloid DCpre and (3) CD11c− plasmacytoid (lymphoid) DCpre. Monocytes can differentiate into cells displaying features of immature DCs or macrophages (MΦ). The immature DCs become mature DCs upon treatment with CD40L and/or LPS or when cultured with a combination of cytokines including TNF, IL-1 and IL-6. CD11c+ myeloid DCpre give rise to interstitial DC (intDC), Langerhans cells (LC) or MΦ depending on local cytokine environment.
CD11c− IL-3Rα+ lymphoid DC precursors are a major source of interferon-alpha (IFN-α). High levels of IFN-α are often found in lupus serum (Kim et al., Clin. Exp. Immunol. 70:562-269, 1987). Furthermore, IFN-α treatment often induces the appearance of autoantiodies and eventually the development of autoimmune diseases including SLE (Ronnblum et al., J. Intern. Med. 227:207-210, 1990). Anti-IFN-α antibody has been reported in SLE patients (Suit et al., Clin. Exp. Rheumatol. 1:133-135).
Plasmacytoid DCs have been reported to produce IFN-α which in turn affects differentiation of myeloid DCs and growth and activation of B cells. Spits et al. (J Exp Med 192(12):1775-84, 2000) and Blom et al. (J Exp Med 192(12):1785-96. 2000) report that CD11c− plasmacytoid DCs are of lymphoid origin in humans. Siegal et al. (Science 284:1835, 1999) report that lymphoid DCs (plasmacytoid DCs) produce large amounts of IFN-α when exposed to inactivated herpes simplex virus. Cella et al., (Nature Medicine 5(8):868-70, 1999) report that lymphoid DCs (plasmacytoid DCs) produce large amounts of IFN-α in response to influenza virus as well as CD40 ligation.
The autoantibodies (autoAbs) in SLE can be characterized in three major categories: (1) anti-nuclear and anti-double stranded DNA antibodies; (2) autoAbs directed against the surface of endothelial cells and platelets (anti-phospholipids/12 glycoprotein); and (3) autoAbs directed against molecules on the surface of hematopoietic cells (see, e.g., review of Cabral and Alarcon-Segovia (1998) Curr. Opin. Rheumatol. 10:409). In addition to the direct damage caused by cellular and/or tissue antigen-antibody interactions, many of the disease's symptoms result from indirect damage through the deposition of immune complexes on tissues. This mechanism has been shown to be responsible for some forms of SLE nephritis, arthritis, and vasculitis (Laihta, R. G. 1999. Systemic Lupus Brythematosus. Academic Press; Kammer, G. M., and G. C. Tsokos. 1999. Lupus, Humana Press). Defects in immune complex clearance, including include Fc receptor (“FcR”) and C3b-receptor (“C3b-R”) dysfunction, as well as genetic defects in complement proteins and C-reactive protein (all of which are essential players in the removal of anti-DNA/nucleosome complexes) can contribute to the development of SLE (Lahita, R. G. 1999. Academic Press; Kammer, G. M., and G. C. Tsokos. 1999 Humana Press). B cells play a major role in SLE pathogenesis, as they are responsible for the production of autoantibodies and hypergammaglobulinemia.
Hooks et al. (N. Engl. J. Med. 301:5, 1979) describe the presence of circulating immune interferon in patients with autoimmune disease including SLE. Kim et al. disclosed that the levels of IFN-α correlated with the clinical activity index. Preble et al. (J. Exp. Med. 157:214, 1983) and von Wussow et al. (Arthritis Rheum. 32:914, 1989) disclose that high levels of 2-5A synthetase and MX protein, two proteins specifically induced by IFN-α, are found in the mononuclear cells of both serum IFN-positive and serum IFN-negative SLE patients. Vallin et al. (J. Immunol. 163:6306 1999) disclose that the IFN-α inducing factor acts on leukocytes with features of immature DCs. Batteux et al. (Eur. Cytokine Netw. 10:509, 1999) disclose that the induction of IFN-α production by SLE serum is dependent on FcγRII (CD32).
One complication of IFN-α therapy is the induction of autoimmune disorders (in about 4% to 19% of the cases), the most common being thyroid dysfunction (Bhrenstein et al., Arthritis Rheum. 36:279, 1993; Okanoue et al., J. Hepatol. 25:283, 1996; Ronnblom et al., Ann. Intern. Med. 115:178, 1991; Kalkner et al., Qjm. 91:393, 1998). Indeed, Schilling et al. (Cancer 68:1536, 1991) disclose that IFN-α a therapy can also induce SLE with a frequency of 0.15% to 0.7%. Every case is associated with the induction or marked increase in titers of antinuclear antibodies and anti-DNA antibodies.
Type I diabetes is another autoimmune disease in which IFN-α plays an important etiopathogenic role. Foulis et al. (Lancet 2:1423, 1987) and Huang et al. (Diabetes 44:658, 1995) disclose a strong correlation between the expression of IFN-α by the pancreatic islets and the development of autoimmune diabetes in humans. Furthermore, Chakrabarti et al. (J. Immunol. 157:522, 1996) disclose that expression of IFN-α by B cells within pancreas Langerhans islets causes diabetes in a transgenic mouse model. Additionally, Fabris et al. (Lancet 340:548, 1992) and Guerci et al. (Lancet 343:1167, 1994) disclose that IFN-α therapy can induce Type I diabetes in humans.
FMS-like tyrosine kinase 3 (“Flt3”) is a member of the type III tyrosine kinase receptor family which also includes KIT (c-kit RTK), FMS (M-CSF RTK) and platelet-derived growth factor (PDGF) receptor. Similar to the ligands for the KIT and FMS receptors, stem cell factor and M-CSF, respectively, the Flt3 receptor is activated by a cognate molecule, termed Flt3-ligand (“Flt3L”). Flt3 is a variant form of a tyrosine kinase receptor that is related to the c-fms and c-kit receptors (Rosnet et al. Oncogene, 6,1641-1650, 1991). Flt3L is a hematopoietic cytokine that has been shown to facilitate the expansion of DCs and the generation of antitumor immune responses (see U.S. Pat. No. 5,554,512, “Ligands for Flt3 Receptors”). Flt3L has been found to regulate the growth and differentiation of progenitor and stem cells (Blazar et al. (2001) Biology of Blood and Marrow Transplantation 7:197-207 and see U.S. Pat. No. 5,843,423). Flt3L treatment of monocyte cell cultures was shown to result in a marked expansion in the absolute number of myeloid- and lymphoid-related DCs and a reduction in the proportion of donor splenic T cells (Blazar et al).
All of the disclosures of the publications which are referred to within this application (including U.S. patents, published PCT applications, scientific references, books, manuals, etc.) are hereby incorporated by reference in their entireties into this application.